E. Antonio Chiocca, M.D. Ph.D. ~ Research Activities in the Neurosurgical Service at MGH

Members of the Chiocca
Laboratory (1997-1999):

Richard Chung, MD PhD

Manish Aghi, BS

Xiaoqun Jiang, MD

Yoshinaga Saeki, MD PhD

Edward Smith, MD

Keiro Ikeda, MD PhD

Nazer Qureshi, MD

Thomas Deisboeck, MD

Tomotsogu Ichikawa, MD PhD

Maureen Chase, BS

Kristen Suling, BS

Hiroaki Wakimoto, MD PhD

Nuzhat Husain, MD

The NIH-funded laboratory of E. Antonio Chiocca, MD PhD, has been interested in defining the molecular mechanisms through which mutant (replication-conditional, oncolytic, replication-compromised, replication-restricted) viruses interact and destroy tumor cells, in the brain and/or other organs. A number of different viruses possess genes that can be deleted or whose expression can be altered so that they will primarily grow and kill tumor cells, while sparing normal tissues (see Boviatsis et al., 1994). Currently, we are further refining the tumor-selectivity of a mutant virus based on herpes simplex virus type I (HSVI). This is being done through tumor-specific promoter/enhancer elements in order to modulate viral growth and/or by deleting/altering viral genes whose proteins interact with cellular/tumor factors in order to complement viral gene defects (Chung and Chiocca, unpublished). Additional studies are being carried out to try and define potential interactions between cellular pathways involved in neoplastic transformation and viral genes needed for the viral life cycle.

These mutant viruses can also be engineered to function as gene therapy vectors. In one example, we have engineered a gene (CYP2B1) into the HSV1 genome that confers susceptibility to the chemotherapy and immunomodulating agents, cyclophosphamide/ifosfamide (Wei et al., 1994 and 1995). This new viral mutant not only replicates in and kills tumor cells in a relatively selective fashion, but it also endows tumor cells with the capability of converting cyclophosphamide/ifosfamide into their active anticancer agents, thereby amplifying the viral oncolytic effect (Chase et al., 1998).

The large capacity of the HSV genome further enables us to engineer additional anticancer functions into it. In one strategy, 2 or 3 genes, each responsible for the activation of a different chemotherapy agent, can be placed into the mutant virus to achieve synergistic, multimodal cancer therapy (Aghi et al., 1998, Aghi and Chiocca, unpublished results, Ichikawa and Chiocca, unpublished results). The ultimate tests for this type of work will be provided not only by assays in animal models of invasive tumors of the brain (Ichikawa and Chiocca, unpublished), but also in complex models of tumor growth dynamics (Deisboeck and Chiocca, unpublished).

One of the features that remains to be explored with this type of research relates to the interaction between the immune system and the mutant virus that is infecting and/or is propagating within a neoplastic mass. This interaction involves multiple components of the immune system, including both humoral (innate and elicited) and cellular arms. We have started to characterize these components, in order to define which type of immune responses help and which hinder the viral oncolytic effect (Ikeda and Chiocca, unpublished results). This is an important question because it will provide us with knowledge that can affect the success and safety of this type of anticancer treatment.

Although oncolytic HSV can efficiently kill tumor cells, it can also be engineered to become almost completely devoid of all viral genes so that it can be used as a gene transfer vector for neurons without harming them. Using bacterial artificial chromosomes, we can package cDNAs into HSV capsids, eliminating all viral gene expression (Saeki et al., 1998). These constructs can then efficiently transfer genes into neurons in brains. Additional refinements of this technology is in progress with the aim of delivering genes in the form of cDNAs or, more excitingly, as complete genomic sequences (Saeki and Chiocca, unpublished).